Submissions for variant NM_001032386.2(SUOX):c.228G>T (p.Arg76Ser)

gnomAD frequency: 0.00057  dbSNP: rs202085145

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000351081	SCV000380307	uncertain significance	Sulfite oxidase deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Precision Medicine, Vanderbilt University Medical Center	RCV000351081	SCV000889983	pathogenic	Sulfite oxidase deficiency	2018-03-16	criteria provided, single submitter	research
Invitae	RCV000351081	SCV001030443	benign	Sulfite oxidase deficiency	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002522240	SCV003752897	benign	Inborn genetic diseases	2022-03-10	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488520	SCV004241048	likely benign	not specified	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: SUOX c.228G>T (p.Arg76Ser) results in a non-conservative amino acid change in the encoded protein sequence and is within the exonic splice region. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 250708 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in SUOX causing Sulfite Oxidase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.228G>T in individuals affected with Sulfite Oxidase Deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on splicing, suggesting the variant resulted in reduced normal transcript at about 39% of WT and the exon-skipped transcript was significantly enhanced by RT-PCR in HEK293T cells, however such data conflict with the subsequent presentation in the same paper, which does not allow convincing conclusions about the variant effect (Bastarache_2018). The following publication have been ascertained in the context of this evaluation (PMID: 29590070). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Pathogenic, n=1; Uncertain significance, n=1; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000351081	SCV004563089	uncertain significance	Sulfite oxidase deficiency	2023-09-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003920288	SCV004740168	likely benign	SUOX-related condition	2021-01-02	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).